Professional Documents
Culture Documents
Oxytocin, Methylergonovine,
Carboprost, Misoprostol
KEYWORDS
Oxytocin Methylergonovine Carboprost Misoprostol Uterine atony
Uterotonic agent Postpartum hemorrhage
KEY POINTS
Uterotonic agents are widely used in the prevention and treatment of postpartum hemor-
rhage, and although oxytocin remains the first-line agent, a standardized guideline for
optimal dose and rate of administration has not been clearly defined.
Methylergonovine is a highly effective second-line agent; however, it is associated with
severe vasoconstriction and is contraindicated for hypertensive patients.
Carboprost is useful for escalation of treatment when oxytocin and uterine massage have
been insufficient to restore uterine tone, especially when methylergonovine is contraindi-
cated, but it can cause severe bronchospasm and is thus contraindicated in patients with
asthma.
Misoprostol is characterized by low cost, stability in storage, broad availability, minimal
side effects, ease of administration, and multiple medical uses; however, recent studies
have called into question its effectiveness as an adjunct uterotonic agent, limiting its
role to scenarios in which other, injectable uterotonics are not readily available or easily
administered.
OXYTOCIN
Introduction
Oxytocin, the first-line agent in the prevention and treatment of postpartum hemor-
rhage, is a polypeptide structure that is produced in the paraventricular nucleus of
the hypothalamus and released by the posterior pituitary gland. It was first discovered
by Sir Henry Dale in 1909 when he discovered that a hormone from the pituitary gland
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
2 Vallera et al
caused uterine contractions in a pregnant cat.1 It was the first polypeptide hormone
synthesized in 1953 by the American biochemist, Vincent Du Vigneaud.2 Oxytocin re-
mains the first-line agent in the management and prevention of uterine atony after
vaginal and operative delivery. The clinical roles of oxytocin in the obstetric population
include induction and augmentation of labor, and prevention and treatment of post-
partum uterine atony.
Structure/Activity
Oxytocin is a short polypeptide consisting of 9 peptides (nonapeptide). Its chemical
structure is C46H66N12O12S2, which is structurally similar to vasopressin, and both
are secreted by the posterior pituitary gland. A disulfide bridge connects 2 cystines
in the primary sequence (Cys1 and Cys 6), forming a ring.3
Oxytocin exerts a stimulatory effect on myometrial contractility by increasing the
intracellular concentration of calcium. This process is achieved by the release of cal-
cium in the sarcoplasmic reticulum and by enhanced entry of extracellular calcium.
Oxytocin binds to a G-protein on the surface of the uterine myocyte, resulting in the
generation of diacylglycerol (DAG) and inositol triphosphate (IP3) via phospholipase
C on phosphatidyl-inositol bisphosphate.4 DAG stimulates prostaglandin synthesis,
which also contributes to uterine contractions. IP3 stimulates the release of calcium
from the sarcoplasmic reticulum and increases the concentration of cytoplasmic cal-
cium.5 For sufficient activation of myometrial contraction, this increase in intracellular
calcium from the sarcoplasmic reticulum alone is not sufficient and entry of extracel-
lular calcium is required. This process is mediated by the oxytocin–G-protein complex,
which causes a conformational change in voltage-gated calcium channels allowing
the influx of extracellular calcium. Calcium then binds to calmodulin and activates
myosin light-chain kinase, which is the fundamental contraction mechanism of uterine
smooth muscle.6
The rate-limiting step for the action of oxytocin is the concentration of oxytocin re-
ceptors on the myometrium. Of note, the oxytocin receptor is absent in a nonpregnant
uterus. Once a woman becomes pregnant, oxytocin receptors appear in myometrial
cells at approximately 13 weeks’ gestation and increase in concentration until term.
The distribution of oxytocin receptors in the uterus is not uniform throughout. There
is a higher concentration of receptors in the fundus of the uterus, and the concentra-
tion decreases closer to the lower uterine segment and cervix.5 This uneven receptor
distribution may explain the less prominent uterine contraction seen in the lower third
of the uterus after administration of oxytocin.
Pharmacokinetics
Oxytocin is absorbed via intravenous, intramuscular, buccal, or nasal mucosal routes,
but it is most commonly administered intravenously to allow for precise dosing and
rapid discontinuation if adverse reactions occur. Intravenous injection has an immedi-
ate onset of action compared with intramuscular injection, which takes approximately
3 to 7 minutes.7 The recommended dose for intramuscular injection during cesarean
delivery is 10 units after delivery of the placenta. Once absorbed, oxytocin redistrib-
utes to the extracellular space and does not bind to plasma proteins. The half-life of
oxytocin is 10 to 12 minutes. There is a linear increase in plasma concentration of
oxytocin after a continuous infusion. It takes approximately 20 to 30 minutes to reach
a steady-state in plasma,8 and a maximum concentration is reached in approximately
40 minutes.9
Although the mechanism of oxytocin degradation is not clearly elucidated, there are
2 proposed pathways that contribute to oxytocin metabolism, which involve cysteine
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Uterotonic Medications 3
Clinical Role
Uterine atony is the most common cause of severe postpartum hemorrhage. Conse-
quently, the use of uterotonic agents is crucial to reducing the risk of postpartum hem-
orrhage and improving maternal safety. Oxytocin is the drug of choice for prevention
and treatment of uterine atony after vaginal and operative deliveries. It is also widely
used to induce and augment the labor process.
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
4 Vallera et al
given for inadequate tone and uterine atony continues, then a second-line uterotonic
agent is recommended. The “Rule of Threes” algorithm minimizes the total dose of
oxytocin administered and may represent an optimal regimen for elective cesarean
deliveries.
Side Effects and Contraindications
Oxytocin used for prophylaxis or treatment of postpartum hemorrhage during cesar-
ean delivery may result in several side effects. The adverse effects include hemody-
namic instability (hypotension, tachycardia, myocardial ischemia, and arrhythmias),
nausea, vomiting, headache, and flushing. The most common side effects are hypo-
tension and tachycardia and are related to the dose and rate of administration. Hypo-
tension is predominately caused by transient relaxation of vascular smooth muscle
cells via calcium-dependent stimulation of the nitric oxide pathway, which leads to pe-
ripheral vasodilation, hypotension, and a compensatory increase in heart rate, stroke
volume, and cardiac output.17 These cardiovascular effects may be well tolerated in a
healthy patient but caution must be taken when administering to patients with
abnormal ventricular function, valvular stenosis, or hypovolemia.4 Due to its structural
similarity to vasopressin, oxytocin administered in high dosages may lead to water
intoxication, hyponatremia, seizures, and coma.18
Summary
Oxytocin remains the first-line agent for prevention and treatment of postpartum hem-
orrhage after vaginal and cesarean delivery. Adverse side effects leading to cardiovas-
cular instability are dose and rate related. Currently, there are no standardized
administration guidelines for the administration of oxytocin, but a “Rule of Threes” al-
gorithm may be a safe method for oxytocin use during elective cesarean deliveries.
Although oxytocin has been used safely and effectively by obstetricians and anesthe-
siologists for many years, the benefits of oxytocin must be weighed against potentially
serious side effects.
METHYLERGONOVINE
Introduction
Methylergonovine has a long history of use for the treatment of postpartum hemor-
rhage due to uterine atony. It is a semisynthetic amide ergot derivative, which pro-
duces sustained contraction of the uterus without causing significant systemic
vasoconstriction in most cases.19 The American College of Obstetricians and Gyne-
cologists recommends methylergonovine as a second-line uterotonic for refractory
uterine atony.20 However, in 2012, the Food and Drug Administration (FDA) raised po-
tential safety concerns about methylergonovine-induced vasoconstriction causing
myocardial ischemia and infarction, which led to a revision of the methylergonovine
label.21
Structure/Activity
Ergot alkaloids were first isolated from ergot fungi and are derivatives of the tetracyclic
compound 6-methylergoline.19 Methylergonovine maleate (9,10-didehydro-N-[(S)-(1-
hydroxymethyl) propyl]-6-methylergoline-8beta-carboxamide maleate salt) is a
semisynthetic ergot alkaloid that is produced by a reaction of (1)-lysergic acid with
L-(1)-aminobutanol.22 Methylergonovine has low water solubility and is prepared as
a water-soluble maleate salt.23 Exposure to water or light leads to the formation of
6-hydroxy derivatives, which will be expedited in an acidic environment. It is easily
oxidized, and the oxidation produces a color change. Methylergonovine should be
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Uterotonic Medications 5
Pharmacokinetics
The onset of action of intravenous methylergonovine is nearly immediate. After intra-
muscular injection, the onset is 2 to 5 minutes, and after oral administration the onset
is 5 to 10 minutes. If administered intravenously, methylergonovine is distributed from
plasma to peripheral tissue in 2 to 3 minutes. Peak plasma concentration following
intramuscular injection occurs in approximately 0.4 hour, and occurs approximately
1 hour after oral administration. Plasma levels have a biphasic decline with intramus-
cular absorption.21 The half-life of methylergonovine after intravenous administration
is 2.3 hours and after oral administration is 2.7 hours. The bioavailability is significantly
more variable with oral administration when compared with intravenous or intramus-
cular administration.22 Intramuscular injection had a greater bioavailability than oral
administration, likely due to first-pass metabolism by the liver. Ergot alkaloids are
mainly eliminated by hepatic metabolism.21
Clinical Role
Methylergonovine is used for the treatment postpartum hemorrhage due to uterine
atony or subinvolution. At high doses, it creates sustained contractions in the
uterus.23,24 The American College of Obstetricians and Gynecologists (ACOG)
recommends methylergonovine as a second-line uterotonic.20 When compared with
carboprost, methylergonovine has been associated with reduced risk of hemorrhage-
related morbidity in women with uterine atony refractory to oxytocin.26 Recently,
methylergonovine has also been used to treat migraines and cluster headaches and
to produce diagnostic coronary vasospasm in patients with variant angina.24,27
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
6 Vallera et al
CARBOPROST
Introduction
Carboprost (US brand name Hemabate) is an analog of prostaglandin F2a. Maternal
concentrations of endogenous prostaglandins increase during labor, with peak con-
centrations occurring at the time of placental separation. This prostaglandin surge
likely contributes to uterine contractions and placental delivery. One cause of uterine
atony may be a deficiency of prostaglandin F2a concentration increase during the
third stage of labor.31,32
Structure/Activity
Rapid metabolism of naturally occurring prostaglandins limited their usefulness for
clinical application and led to the development of analogs with longer durations of ac-
tion. Carboprost tromethamine, the active ingredient in Hemabate, is an analog of
15-methyl prostaglandin F2a. Naturally occurring prostaglandins are oxidized at car-
bon 15, which causes rapid inactivation of primary prostaglandins. On the analog, this
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Uterotonic Medications 7
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
8 Vallera et al
MISOPROSTOL
Introduction
Misoprostol, a synthetic analog of prostaglandin E1, has a long history of medical
application. Naturally occurring prostaglandin E1 (PGE1) protects gastric mucosa
through reduction in gastric acid secretion and stimulation of mucus and bicarbonate
secretion. Originally developed as a treatment for peptic ulcers, misoprostol found a
vital role in obstetric and gynecologic patients thanks to its effects on uterine smooth
muscle and the cervix. The list of clinical applications has since grown to include medi-
cally induced abortion, medically assisted evacuation after miscarriage, cervical
ripening, induction of labor, and treatment of uterine atony.
Structure/Activity
Misoprostol is a synthetic prostaglandin E1 analog (15-deoxy-16-hydroxy-16-methyl
PGE1). Compared with PGE1, misoprostol exhibits superior performance across 3
notable areas. PGE1 is rapidly metabolized, which hinders its utility via oral and paren-
teral routes, and it also produces more side effects while being less chemically stable.
PGE1 has a carboxyl group at carbon 1 and a hydroxyl group at carbon 15. Misopros-
tol improves on the characteristics of PGE1 by having a methyl ester at carbon 1
(imparting greater duration of action), a carbon 16 methyl group, and hydroxyl group
at carbon 16 rather than carbon 15. The modifications at carbon 16 increase oral ac-
tivity, duration of action, and safety.42
Pharmacokinetics
Misoprostol has differing pharmacokinetic profiles depending on the route of admin-
istration, and clinically useful routes include the following: oral, buccal, sublingual,
vaginal, and rectal. In terms of speed of onset, the oral and sublingual routes appear
to be superior. Sublingual administration yields the highest peak plasma concentra-
tions of any route, and peak plasma concentrations are seen in approximately 30 mi-
nutes.43 Concomitant food intake and antacid use will measurably reduce the
availability of oral misoprostol, but it is not clear whether the effect is clinically
significant.44
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Uterotonic Medications 9
Clinical Role
Misoprostol is a second-line agent for treatment of uterine atony. During and after the
third stage of labor, oxytocin is the first-line agent given to all patients to prevent post-
partum hemorrhage. In situations in which oxytocin is not immediately available, or
when oxytocin fails to produce a desired result, methylergonovine has advantages
of speed and efficacy over misoprostol. However, in patients with a contraindication
to methylergonovine therapy, or in environments in which skilled attendants and sup-
plies are not available to deliver injectable medications, or if methylergonovine is not
immediately available, misoprostol can be used.51 In medically underserved areas
where the supply and storage of expensive, or light-sensitive or temperature-
sensitive medications is limited, misoprostol tablets offer an inexpensive and easy-
to-store uterotonic option.52 Misoprostol also can be given to patients whose uterine
atony is refractory to earlier interventions,53 but in a major meta-analysis there was no
clear benefit to using misoprostol as an adjuvant to oxytocin in terms of major out-
comes, such as mortality and blood loss.54
In a meta-analysis of recent large randomized controlled trials involving misoprostol
versus placebo, misoprostol effectively prevented postpartum hemorrhage and se-
vere postpartum hemorrhage by 24% and 41%, respectively.55
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
10 Vallera et al
SUMMARY
Conditions that increase the risk of uterine atony, such as overdistention of the uterus
(as seen with multiple gestations and polyhydramnios), magnesium sulfate administra-
tions and chorioamnionitis are frequently encountered in clinical practice. With the
incidence of postpartum hemorrhage increasing and with uterine atony a contributor
in many cases, it is important to understand the risks and benefits of commonly used
uterotonic agents.59 Manual uterine massage and oxytocin are almost universally
accepted as the first-line treatments of choice for uterine atony. When this combina-
tion is ineffective, it is often appropriate to administer a second-line uterotonic agent.
Methylergonovine and carboprost are second-line agents in most treatment proto-
cols. The choice of which therapeutic agent to use should be based on the comorbid-
ities of the patient and the clinical judgment of the practitioners involved in the case.
Misoprostol remains a treatment option for uterine atony, but its utility as an adjunct to
the other uterotonic medications may be limited.
REFERENCES
1. Dale HH. The action of extracts of the pituitary body. Biochem J 1909;4:427–47.
2. Du Vigneaud V, Ressler C, Swan JM, et al. Oxytocin: synthesis. J Am Chem Soc
1954;76(12):3115–8.
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Uterotonic Medications 11
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
12 Vallera et al
24. Gao Y, Sun Q, Liu D, et al. A sensitive LC-MS/MS method to quantify methylergo-
novine in human plasma and its application to a pharmacokinetic study.
J Chromatogr B Analyt Technol Biomed Life Sci 2016;1011:62–8.
25. Gizzo S, Patrelli TS, Gangi SD, et al. Which uterotonic is better to prevent the
postpartum hemorrhage? Latest news in terms of clinical efficacy, side effects,
and contraindications: a systematic review. Reprod Sci 2013;20(9):1011–9.
26. Butwick AJ, Carvalho B, Blumenfeld YJ, et al. Second-line uterotonics and the risk
of hemorrhage-related morbidity. Am J Obstet Gynecol 2015;212:642.e1-7.
27. Saper JR, Evans RW. Oral methylergonovine maleate for refractory migraine and
cluster headache prevention. Headache 2013;53(2):378–81.
28. Kuczkowski KM. Myocardial ischemia induced by intramyometrial injection of
methylergonovine maleate. Anesthesiology 2004;100(4):1043.
29. Bateman BT, Huybrechts KF, Hernandez-Diaz S, et al. Methylergonovine maleate
and the risk of myocardial ischemia and infarction. Am J Obstet Gynecol 2013;
209(5):459.e1–13.
30. Bateman BT, Tsen LC, Liu J, et al. Patterns of second-line uterotonic use in a large
sample of hospitalizations for childbirth in the United States: 2007-2011. Anesth
Analg 2014;119(6):1344–9.
31. Noort WA, van Bulck B, Vereecken A, et al. Changes in plasma levels of PGF2a
and PGI2 metabolites at and after delivery at term. Prostaglandins 1989;37:3–12.
32. Fuchs AR, Husslein P, Sumulong L, et al. The origin of circulating 13,14-dihydro-
15-keto-prostaglandin F2a during delivery. Prostaglandins 1982;24:715–22.
33. Bygdeman M. Pharmacokinetics of prostaglandins. Best Pract Res Clin Obstet
Gynaecol 2003;17:707–16.
34. Hayashi RH, Castillo MS, Noah ML. Management of severe postpartum hemor-
rhage with a prostaglandin F2a analogue. Obstet Gynecol 1984;63:806–8.
35. Izumi H, Garfield RE, Morishita F, et al. Some mechanical properties of skinned
fibres of pregnant human myometrium. Eur J Obstet Gynecol Reprod Biol
1994;56:55–62.
36. Pfizer. Hemabate (carboprost tromethamine). U.S. Food and Drug Administration.
2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/
017989s019lbl.pdf. Accessed August 22, 2016.
37. Bigrigg A, Chissell S, Read MD. Use of intra myometrial 15-methyl prostaglandin
F2a to control atonic postpartum haemorrhage following vaginal delivery and fail-
ure of conventional therapy. Br J Obstet Gynaecol 1991;98:734–6.
38. O’Leary AM. Severe bronchospasm and hypotension after 15-methyl prosta-
glandin F2a in atonic postpartum haemorrhage. Int J Obstet Anesth 1994;3:42–4.
39. Andersen LH, Secher NJ. Pattern of total and regional lung function in subjects
with bronchoconstriction induced by 15-methyl PGF2a. Thorax 1976;31:685–92.
40. Cooley DM, Glosten B, Roberts JR, et al. Bronchospasm after intramuscular 15-
methyl prostaglandin F sub 2 alpha, 125 micrograms, and intravenous oxytocin,
20 units, for the control of blood loss at elective cesarean section. Am J Obstet
Gynecol 1994;171:1356–60.
41. Harper C, Levy D, Chidambaram S, et al. Life-threatening bronchospasm after
intramuscular carboprost for postpartum hemorrhage. BJOG 2007;114:366–8.
42. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol. Pharmacokinetic profiles,
effects on the uterus, and side-effects. Int J Gynecol Obstet 2007;99:S160–7.
43. Tang OS, Schweer H, Seyberth HW, et al. Pharmacokinetics of different routes of
administration of misoprostol. Hum Reprod 2002;17:332–6.
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
Uterotonic Medications 13
44. GD Searle & Co. Cytotec (misoprostol). U.S. Food and Drug Administration.
2002. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/
19268slr037.pdf. Accessed August 12, 2016.
45. Zieman M, Fong SK, Benowitz NL, et al. Absorption kinetics of misoprostol with
oral or vaginal administration. Obstet Gynecol 1997;90:88–92.
46. Meckstroth KR, Whitaker AK, Bertisch S, et al. Misoprostol administered by
epithelial routes. Obstet Gynecol 2006;108:82–90.
47. Schaff EA, DiCenzo R, Fielding SL. Comparison of misoprostol plasma concen-
trations following buccal and sublingual administration. Contraception 2005;71:
22–5.
48. Khan RU, El-Refaey H. Pharmacokinetics and adverse-effect profile of rectally
administered misoprostol in the third stage of labor. Obstet Gynecol 2003;101:
968–74.
49. Abdel-Aleem H, Villar J, Gulmezoglu AM, et al. The pharmacokinetics of the pros-
taglandin E1 analogue misoprostol in plasma and colostrum after postpartum oral
administration. Eur J Obstet Gynecol Reprod Biol 2003;108:25–8.
50. Vogel D, Burkhardt T, Rentsch K, et al. Misoprostol versus methylergometrine:
pharmacokinetics in human milk. Am J Obstet Gynecol 2004;191:2168–73.
51. POPPHI. Fact sheets: uterotonic drugs for the prevention and treatment of post-
partum hemorrhage. Seattle (WA): PATH; 2008.
52. McCormick ML, Sanghvi HC, Kinzie B, et al. Preventing postpartum hemorrhage
in low-resource settings. Int J Gynaecol Obstet 2002;77:267–75.
53. Blum J, Alfirevic Z, Walraven G, et al. Treatment of postpartum hemorrhage with
misoprostol. Int J Gynaecol Obstet 2007;99(Suppl 2):S202–5.
54. Mousa HA, Blum J, Abou EL, et al. Treatment for primary postpartum hemor-
rhage. Cochrane Database Syst Rev 2014;(2):CD003249.
55. Oladapo OT. Misoprostol for preventing and treating postpartum hemorrhage in
the community: a closer look at the evidence. Int J Gynaecol Obstet 2012;119:
105–10.
56. Hofmeyr J, Gulmezolgu AM, Novikova N, et al. Misoprostol to prevent and treat
postpartum haemorrhage: a systematic review and meta-analysis of maternal
deaths and dose-related effects. Bull World Health Organ 2009;87:666–77.
57. Hofmeyr GJ, Gulmezoglu AM, Novikova N, et al. Postpartum misoprostol for pre-
venting maternal mortality and morbidity. Cochrane Database Syst Rev
2013;(7):CD008982.
58. Lumbiganon P, Hofmeyr J, Gulmezoglu AM, et al. Misoprostol dose-related shiv-
ering and pyrexia in the third stage of labour. WHO Collaborative Trial of Miso-
prostol in the Management of the Third Stage of Labour. BJOG 1999;106:304–8.
59. Bateman BT, Berman MF, Riley LE, et al. The epidemiology of postpartum hem-
orrhage in a large, nationwide sample of deliveries. Anesth Analg 2010;110(5):
1368–73.
Downloaded for Anonymous User (n/a) at Sociedade Brasileira de Anestesiologia from ClinicalKey.com by Elsevier on May 15, 2017.
For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.